A central focus of the COGA project is the identification of specific genes in which variations affect the risk for alcohol dependence and related phenotypes. We will continue these successful efforts, with increased focus on the interplay of genes and environment. We will examine how these variants, identified in one generation, affect important precursor phenotypes during the critical adolescent phase of the next generation, and how environment modulates the effects. We will devote more effort to characterizing the mechanism of action of the variants that we identify, working at molecular, cellular and developmental levels. A new aim will be to examine the hypothesis that exposure to alcohol during key developmental stages causes epigenetic modifications that have long-term impact on the risk for alcoholism and its sequelae. These aims are interrelated, and each contributes to the overall goals of identifying genes that affect alcoholism and related phenotypes and of understanding how the genes contribute to this risk. We anticipate that this knowledge will contribute to the development of more effective interventions to decrease the risk of alcoholism and/or improve treatment of those with alcohol dependence.